Steroid receptor coactivator-3 expression in lung cancer and its role in the regulation of cancer cell survival and proliferation.
Steroid receptor coactivator-3 expression in lung cancer and its role in the regulation of cancer cell survival and proliferation.
复制标题
DOI：
10.1158/0008-5472.can-10-0005
复制
发表时间：
2010-08-15
期刊：
影响因子：
11.2
通讯作者：
Minna JD
中科院分区：
文献类型：
--
作者：
Cai D;Shames DS;Raso MG;Xie Y;Kim YH;Pollack JR;Girard L;Sullivan JP;Gao B;Peyton M;Nanjundan M;Byers L;Heymach J;Mills G;Gazdar AF;Wistuba I;Kodadek T;Minna JD
类固醇受体辅活化子-3(SRC-3)是一种组蛋白乙酰转移酶和核激素受体(NHR)共激活子，位于20q12，在多种上皮性肿瘤中扩增，在乳腺癌中有较好的研究。然而，它在肺癌发病机制中的可能作用尚不清楚。免疫组织化学检测发现27%的非小细胞肺癌患者sRC-3过度表达，与无瘤生存差(p=0.0015)和总生存率(p=0.0008)相关。27%的NSCLC显示SRC-3基因扩增，我们发现肺癌细胞株表达SRC-3的水平高于永生化的人支气管上皮细胞，而永生化的人支气管上皮细胞表达SRC-3的水平高于原代培养的人HBECs。SiRNA介导的SRC-3在高表达(但非低表达)肺癌细胞中的下调显著抑制了肿瘤细胞的生长并诱导了细胞凋亡。最后，我们发现SRC-3的表达与吉非替尼的敏感性呈负相关，并且SRC-3基因敲除导致对EGFR-TKI耐药的肺癌对吉非替尼更加敏感。综上所述，SRC-3可能是肺癌的重要癌基因和治疗靶点。
Steroid receptor coactivator-3 (SRC-3) is a histone acetyltransferase and nuclear hormone receptor (NHR) co activator, located on 20q12, which is amplified in several epithelial cancers and well studied in breast cancer. However, its possible role in lung cancer pathogenesis is unknown. We found SRC-3 over-expressed in 27% of NSCLC patients (N=311) by immunohistochemistry, which correlated with poor disease-free (p=0.0015) and overall (p=0.0008) survival. Twenty-seven percent of NSCLCs exhibited SRC-3 gene amplification, and we found lung cancer cell lines expressed higher levels of SRC-3 than immortalized human bronchial epithelial cells (HBECs), which in turn expressed higher level of SRC-3 than cultured primary human HBECs. siRNA-mediated down-regulation of SRC-3 in high-expressing (but not low expressing) lung cancer cells significantly inhibited tumor cell growth and induced apoptosis. Finally, we found that SRC-3 expression is inversely correlated with gefitinib sensitivity and that SRC-3 knockdown results in EGFR-TKI-resistant lung cancers becoming more sensitive to gefitinib. Together these data suggest that SRC-3 may be an important oncogene and therapeutic target for lung cancer.